It is estimated that more than 60 million people worldwide have been infected by the human immunodeficiency virus since 1982. Nearly half of these infected individuals have died of the resultant Acquired Immunodeficiency Syndrome (AIDS) during the same time frame. Although the virus spread seems to have reached a plateau lately, 2.5 million HIV new infections were reported in 2009. HIV still is a major public health problem. See UNAIDS, 2010 Report on the global AIDS epidemic.
HIV-1 is one of the most genetically diverse viral pathogens described so far. There are three main branches of the HIV-1 phylogenetic tree, the M (main), N (new), and O (outlier) groups. Group M viruses are the most widespread, accounting for more than 99% of global infections. This group is presently divided into nine distinct genetic subtypes, or clades (A through K), based mostly on short env (envelope) gene sequences. See McCutchan F, AIDS 2000; 14(S3):S31-S44 and Robertson D, et al., Science 2000; 288:55-56.
Env is the most variable HIV-1 gene, with up to 35% sequence diversity between clades, 20% sequence diversity within clades, and up to 10% sequence diversity in a single infected person. See Kuiken C, et al., AIDS 1996; 10:31-37 and Shankarappa R, et al., J. Virol. 1999; 73:10489-10502. Clade B is dominant in Europe, the Americas, and Australia. See Kuiken C, et al., AIDS 1996; Am. J. Epidemiol. 2000; 152:814-822. Clade C is common in southern Africa, China, and India and presently infects more people worldwide than any other clade. See McCutchan, 2000, supra. Clades A and D are prominent in central and eastern Africa.
However, many viruses are difficult to classify into clades due to the common intermixing of co-circulating viruses that leads to interclade recombinants. See Heyndrickx L, et al., J. Virol. 200; 74:363-370 and McCutchan F, et al., Virology 1999; 254:226-234. Some recombinant forms have in fact given rise to important epidemic lineages, called circulating recombinant forms (CRFs). The two most common of these are CRF01 (AE), discovered in Thailand, which was initially classified as clade E, though later it was found to be clade E only in env and clade A in other parts of the genome, and CRF02, an AG recombinant form common in Western Africa. See Robertson, 2000, supra. Globally, clades A through D and the CRF01 AE and CRF02 AG recombinants account for more than 90% of global infections.
Neutralizing antibodies (nAbs) against viral envelope proteins (Env) are a first line of adaptive immune defense against HIV-1 exposure by blocking the infection of susceptible cells. See Kwong P, et al., Nature 1998; 393:648-659, Moore J, et al., J. Virol. 1994; 68:469-484, Moore P, et al., J. Virol. 1996; 70:1863-1872, and Parren P, et al., AIDS 1999; 13:S137-S162. The efficacy of vaccines against several viruses has been attributed to their ability to elicit nAbs. See Burton D, Nat. Rev. Immunol. 2002; 2: 706-713 and Zinkerangel R, et al., Adv. Immunol. 2001; 79:1-53. However, there has been limited progress towards the development of effective HIV-1 immunogens despite enormous efforts. See Burton, 2002, supra, McMichael A, Hanke T, Nat. Med. 2003; 9:874-880, and Moore, 1996, supra. The design of these immunogens requires the identification of epitopes capable of inducing better nAb responses. Unfortunately, all attempts to develop immunogens that elicit broadly nAbs responses have failed to the present.
Thus, there is a need in the art for new HIV-1 immunogens capable of inducing better nAb responses.